In A Nutshell: Endometrial Cancer Molecular Subtypes

June 21, 2024

In recent years, molecular subtypes have played an increasingly important role in classifying endometrial cancers and driving important clinical decisions. Join us as Dr. Tashanna Myers, Division Chief, Gynecologic Oncology and Vice Chair Academic Affairs for the Department of OB/GYN at Baystate Medical Center, discusses the key molecular subtypes to provide you with a better understanding of the basics.

00:00:00:00 - 00:00:27:02
Unknown
Hello, everyone, and welcome to our program. In a nutshell, endometrial cancer, Molecular subtypes. I'm Kitty Silverman, the uterine cancer program director at SHARE. Before the program begins, I'd like to tell you a little bit about share. We're a national nonprofit that supports, educates and empowers anyone who has been diagnosed with breast or gynecologic cancers and provides outreach to the general public about signs and symptoms.

00:00:27:04 - 00:01:01:05
Unknown
Now, I'd like to hand it over to the to today's speaker, Dr. Meyers, to introduce herself. Hi. Good afternoon. I'm Shannon Myers. I'm the chief of gynecologic oncology at Baystate Health in Springfield, Massachusetts. Thanks so much for joining us, Dr. Meyers. I'd like to start off by asking you to give a short overview of the molecular classification shown on the slide, and then I'll follow up by asking you a few more specific questions.

00:01:01:07 - 00:01:41:04
Unknown
Absolutely. So in this slide, I go over the molecular classification for endometrial cancer. Broadly, there are four categories in which the majority of tumors will fall into. The first column is pole mutated, and this prognosis tends to be the best. The potential alterations in treatment can be a de-escalation or no adjuvant treatment. These patients tend to be a little bit thinner, have earlier stage and predominantly endometrium histology and all the grades from 1 to 3.

00:01:41:06 - 00:02:21:23
Unknown
We typically will identify this through next generation sequencing. Category two would be MSI High. These are also called MSA hyper mutant, hyper mutated. The prognosis is intermediate and the potential treatment options would be immunotherapy or PD-L1 inhibitors. Clinically, these patients will have lynch syndrome, which is an inherited syndrome. Histologic subtypes again and a be treated histology predominantly grades one through three and this can be diagnosed in two ways IHT immunohistochemistry or by next generation sequencing in the third category.

00:02:22:00 - 00:02:54:14
Unknown
And as he is, probably represents more than 50% of our patients and it's no specific molecular profile. So essentially these are the patients that have the absence of the other categories. It's intermediate prognosis and higher BMI in these patients. Estrogen receptor positive predictive, Huntly, low grade endometrium. And then really it's a diagnosis of exclusion. And then P53 abnormal, unfortunately, has a slightly worse prognosis.

00:02:54:16 - 00:03:20:08
Unknown
And the potential treatment options include chemotherapy or targeted therapies. These patients are going to be lower, have a lower BMI and present at later stage, and these histology are going to be really more aggressive. So grade three and then be treated. No, sorry, serious, clear cells. Our diagnostic tests are going to include immunohistochemistry and Next-Gen sequencing.

00:03:20:10 - 00:03:50:11
Unknown
Thank you very much. That was terrific. What my first question actually is how and when did these classifications start getting used and what has the overall significant gains been in regard to endometrial cancer treatment? Right. So it's a really exciting time in individual cancers. So this data was first published in 2013. The Cancer Genome Atlas reported this molecular multi-platform assessment.

00:03:50:13 - 00:04:19:09
Unknown
There were about 370 and a betrayal cancers, 300 of which were endometrial and about 60 were serous tumors. And they did a combination of whole genome and exome. So we could sequencing microsatellite instability, copy number analysis. And they essentially created the second line of this chart, this tcga category. So, so all of the tumors fell into these four categories.

00:04:19:11 - 00:04:54:18
Unknown
And then a few years later, two groups independently said, how do we apply this clinically? And came up with a molecular classification. And so the promise algorithm, and that stands for proactive Maleki low risk classification classifier for individual cancer. And so while the categories are not identically identified, they really did align and we're now further using this in that 20 in 2023, we changed the staging to incorporate this molecular classification.

00:04:54:20 - 00:05:33:22
Unknown
So I'd say we are really moving to use this data clinically and to try to improve outcomes. Was that the change in the Figo staging? Correct. So Okay, Correct. And that really a lot of that was related to including this. Yes. The main changes are going to be the incorporation of this molecular platform. Right. That's interesting. Yeah. I think you touched a little on the testing, but what testing is used to determine these molecular classifications and at what point after the cancer diagnosis do you give these tests?

00:05:33:24 - 00:06:01:19
Unknown
So we're really aiming to have these tests performed at the time of diagnosis. So it can either happen on a biopsy specimen and those specimens tend to be small or at the time of surgery, the testing can be performed in two ways. So immunohistochemistry is the is the simplest form and as well as next generation sequencing. So those are the two main modalities.

00:06:01:21 - 00:06:28:20
Unknown
And what it's helping to guide us is to help to put people into different prognostic categories. Now, it's not fully ready for prime time, but we are least beginning to recognize that there are some tumors that may inherently have a better prognosis and maybe have the opportunity to decrease the aggressiveness of therapy we offer. Thank you. Actually, that leads well into this next question.

00:06:28:22 - 00:07:02:12
Unknown
What's the difference between the next generation sequencing and immuno histo chemistry and what's the standard of care as to, you know, when they are when they are used? So immunohistochemistry is essentially using antibodies to map to certain antigens and then quantify the expression of those antigens. It's in most hospitals, very standard, very routine. And three of the categories can be determined with that testing.

00:07:02:12 - 00:07:59:03
Unknown
So the MSI High and the P53, and obviously if you have the absence, you fall into that nursing P category. Whole mutation has been identified using next gen sequencing. It's not as wide available, which can be a challenge where depending on where you get your care, but it is widely available through next generation sequencing. So at our institution we will primarily do the IAC on the MCI and the P53 and estrogen receptor and for those patients who were really contemplating the aggressiveness of therapy, then we will send next generation sequencing, next generation sequencing is actually looking at the sequence of DNA or RNA to study the genetic variations or mutations in the tumor.

00:07:59:05 - 00:08:31:24
Unknown
And so essentially you can map thousands of genes all at the same time with a small amount of tumor and figure out what are the mutations that that your particular tumor are expressing that could serve as potential targets. Most times in clinical practice, we're doing that in the recurrent setting and not up front. But for patients who present with more advanced age or more aggressive histology, we really recommend doing it earlier so that you can optimize the therapies.

00:08:32:01 - 00:09:04:05
Unknown
Thank you. Actually, that leads in to another question. If if a person's cancer recurs, is it possible that their molecular classification could change? So that's interesting. I think we don't know yet. There are times when the duration of time between the initial diagnosis and the recurrence or so far that you're going to get a new tissue biopsy. And ideally studying that new tumor that has recurred.

00:09:04:07 - 00:09:26:11
Unknown
But we don't know if they're what the percentage of change that happens over time. So it is an interesting question. I think there are times when we do it, if you have enough tumor, that it's not unreasonable to consider reprofiling the tumor to see if the biology has changed because again, these are cancers, they're unregulated and how they multiply.

00:09:26:11 - 00:09:59:17
Unknown
And so genetic variations are highly probable. Thank you. Many of our participants have heard of copy number, low p53 wild type type and p53 mutation. However, they're often confused about the differences between these two. Can you spend a little time explaining those differences, please? So P53 wild type applies to the the p53 gene in its natural or non mutated state.

00:09:59:19 - 00:10:34:03
Unknown
So that's the normal, I guess healthy version of the gene. A mutation in p53 signifies some alteration along that genes mechanism and in endometrial cancer is a marker of poor prognosis. So when we say wild type, it is your natural on mutated state. Okay. Thank you. I know that the A.P. no specific molecular profile category includes the p53 wildtype mutation and copy number low cancer.

00:10:34:06 - 00:11:02:08
Unknown
Does this category also include hormone receptor positive cancers with PIK three CA mutations? Yeah. So this category represents greater than 50% of endometrial cancers, right? So it's not it's not a small number of patients that don't fall into these other categories. The tumors tend to be estrogen driven. They tend to be low grade. However, there also are aggressive cell types that can fall into this category.

00:11:02:08 - 00:11:34:12
Unknown
So those can be your clear cells, your D differentiated, Your mezzanine Afrique like carcinoma is currently the guidelines don't integrate the. So we don't we don't necessarily modify your treatment directly by your molecular subtype. We're still relying heavily on pathologic features. So we're learning what is the level which we can use this information to truly optimize patient care.

00:11:34:14 - 00:12:07:24
Unknown
And then in terms of the pick three C pathway, yes, this pathway is highly active in this category of patients with a low mutation burden to pick 3ca is it tends to be upregulated. Have you seen a change of I know there there are new treatments that have come out, especially in the last few years. Do you see that evolving over the years with each of these categories?

00:12:08:01 - 00:12:42:01
Unknown
Hopefully, you know, to include some more, you know, really good treatments? I really think this is an exciting time for endometrial cancer where precision medicine is going to really be refined and be at its best. I think the idea of just saying you have a grade one endometrium or eight adenocarcinoma is really behind us. You know, the terminology should be you have a grade one MSI high poll, whole mutated p53 wildtype.

00:12:42:01 - 00:13:09:06
Unknown
Right. The nomenclature for how we identify these tumors is really evolving. And therefore, as we get more defined in the tumors, I think we'll be able to then target our therapies appropriately. So yes, I think there's ongoing research now looking at using the molecular classification as a triaging method for therapy. And I think again, we're just beginning to see how we can maximize that.

00:13:09:06 - 00:13:36:18
Unknown
And what's the interplay? What is the interplay of a p53 abnormal and a whole mutated tumor? Right. How do those two balance each other and what becomes the driver? So so I think, yeah, we should we should anticipate that there will be many things coming down the pike very shortly. That's that's great to hear. Excellent. So I think we just have like one minute.

00:13:36:20 - 00:14:03:22
Unknown
So if there's anything else, Dr. Myers, that you would like to add that we haven't covered, please do. And yeah, I think it's important to ask these questions is beyond your grade and stage. The next question should be and what is the molecular classification of my endometrial cancer? Because that really is the language that we're now speaking. That makes a lot of sense.

00:14:03:22 - 00:14:09:15
Unknown
That's that's great. Well, thank you so much. This is really informative and interesting and helpful.

00:14:09:15 - 00:14:23:19
Unknown
for more information about Cher's upcoming educational programs, support groups and helplines, please visit our website at Share Cancer Support that org And thank you so much, Dr. Myers, for joining us today.

00:14:23:21 - 00:14:30:01
Unknown
This concludes our program and thank you so much to everyone who joined in and have a great rest of the day.

00:14:30:01 - 00:14:30:24
Unknown
Thank you.

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